Osteoarthritis (degenerative joint disease) is the most common form of arthritis. It occurs almost universally in the aged and is of significant medical disability in 20% of these cases. The disease is characterized in general by articular cartillage degeneration, abnormal cartilage and bone formation (osteochondrophytic spurs) and cystic changes in subchondral bone. Recent advances have indicated that the pathogenesis is multifactorial, and at least in part, involves impairment of articular cartilage function. Delineation of these defects in man remains difficult because of the relative inability to study changes in chondrocyte function over time. Nevertheless, established organ and cell culture methodologies have been utilized in this laboratory to explore the in vitro behavior of human aged and osteoarthritic cartilage. Our findings indicate that osteoarthritic cartilage and osteochondrophytic spurs synthesized proteoglycans in culture that were more similar than dissimilar to those produced by non-pathologic aged tissue. Preliminary findings suggested that the synthetic molecule differed from those extracted from the endogenous non-synthetic proteoglycan populations. The principal objective of this proposal is to address the hypothesis that in osteoarthritis specific environmental factors affect osteoarthritic cartilage and chondrocytes, modulating the phenotypic expression of the tissue with particular reference to proteoglycans. These factors interacting with cartilage result in the synthesis of proteoglycans which have many of the characteristics of normal proteoglycans. The eventual incorporation of these molecules into the existing cartilage matrix is, however, defective, presumably as a result of proteolytic attack by chondrocyte neutral pH proteinases. The end result is the formation of a defective cartilage matrix which eventually degenerates. Further understanding of osteoarthritic processes in human studies conducted under controlled in vitro microenvironments will hopefully allow development of specific therapeutic agents to prevent, retard or reverse the disease process.